Potassium channels play a key role in regulation of cell membrane potential and modulation of cell excitability. Potassium channels are largely regulated by voltage, cell metabolism, calcium and receptor mediated processes. [Cook, N. S., Trends in Pharmacol. Sciences (1988), 9, 21; and Quast, U., et al, Trends in Pharmacol. Sciences (1989), 10, 431]. Calcium-activated potassium (K.sub.Ca) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of K.sub.Ca channels is regulated by intracellular [Ca.sup.2+ ], membrane potential and phosphorylation. On the basis of their single-channel conductances in symmetrical K.sup.+ solutions, K.sub.Ca channels are divided into three subclasses: large conductance (maxi-K)&gt;150 pS; intermediate conductance 50-150 pS; small conductance&lt;50 pS. Large-conductance calcium-activated potassium (Maxi-K) channels are present in many excitable cells including neurons, cardiac cells and various types of smooth muscle cells. [Singer, J. et al., Pflugers Archiv. (1987) 408, 98; Baro, I., et al., Pflugers Archiv. (1989) 414 (Suppl. 1), S168; and Ahmed, F. et al., Br, J. Pharmacol. (1984) 83,227].
Potassium ions play a dominant role in controlling the resting membrane potential in most excitable cells and maintain the transmembrane voltage near the K.sup.+ equilibrium potential (E.sub.k) of about -90 mV. It has been shown that opening of potassium channels shift the cell membrane potential towards the equilibrium potassium membrane potential (E.sub.k), resulting in hyperpolarization of the cell. [Cook, N. S., Trends in Pharmacol. Sciences (1988), 9, 21]. Hyperpolarized cells show a reduced response to potentially damaging depolarizing stimuli. Maxi-K channels which are regulated by both voltage and intracellular Ca.sup.2+ act to limit depolarization and calcium entry and may be particularly effective in blocking damaging stimuli. Therefore cell hyperpolarization via opening of Maxi-K channels may result in protection of neuronal cells under ischemic conditions.
A range of synthetic and naturally occuring compounds with maxi-K opening activity have been reported. The avena pyrone extracted from avena sativa-common oats has been identified as a maxi-K channel opener using lipid bi-layer technique [International Patent application WO 93/08800, published May 13, 1993]. 6-Bromo-8-(methylamino)imidazo[1,2-a]pyrazine-2-carbonitrile (SCA-40) has been described as a maxi-K channel opener with very limited electrophysiological experiments [Laurent, F. et al., Br. J. Pharmacol. (1993) 108, 622-626]. The flavanoid, Phloretin has been found to increase the open probability of Ca.sup.2+ -activated potassium channels in myelinated nerve fibers of Xenopus laevis using outside-out patches [Koh, D-S., et al., Neuroscience Lett. (1994) 165, 167-170].
A number of substituted oxindoles have been disclosed as neuroanabolic agents by H. Kuch et al in U.S. Pat. Nos. 4,542,148, issued Sep. 17, 1985 and 4,614,739, issued Sep. 30, 1986.
In European patent application EP-477,819 published Jan. 4, 1992 and corresponding U.S. Pat. No. 5,200,422, issued Apr. 6, 1993 to Olesen, et al., a number of benzimidazole derivatives were disclosed as openers of maxi-K channels by using single-channel and whole-cell patch-clamp experiments in aortic smooth muscle cells. Further work was reported by Olesen, et al in European J. Pharmacol., 251, 53-59 (1994).
Stroke is presently recognized as the third leading cause of adult disability and death in the United States and Europe. In the past decade, several therapeutic approaches for the minimization of stroke-related brain damage have been pursued including inhibitors of AMPA/kainate, N-methyl-D-aspartate (NMDA) and adenosine reuptake inhibitors. It is the object of the present invention to provide novel compounds that will modulate potassium channels, in particular, large-conductance calcium-activated potassium (Maxi-K) channels which will be useful in reducing neuronal damage during ischemic stroke.